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The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma

ABSTRACT: The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma

PROVIDER: PRJNA1098849 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28621811_1.fastq.gz	Fastqsanger.gz
	SRR28621811_2.fastq.gz	Fastqsanger.gz
	SRR28621812_1.fastq.gz	Fastqsanger.gz
	SRR28621812_2.fastq.gz	Fastqsanger.gz
	SRR28621813_1.fastq.gz	Fastqsanger.gz

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The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma [RIP-seq]

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The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma [RNA-seq]

Project description:N6-methyladenosine (m6A) modification plays a central role in both RNA and tumor biology. Yet comprehensive m6A epitranscriptome profiling of primary tumors remains uncharted. To fill this gap, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating them with corresponding transcriptome, proteome and extensive clinical annotation. A total of 8,030 genes are marked with m6A modification, with variable abundances across tumors. Distinct clusters and genes were found to be linked exclusively to disease progression through m6A, rather than mRNA or protein levels. In comparison with NL tissues, 430 transcripts were hypo-methylated in tumors, and 222 were hyper-methylated. Fully 69% of these had no influence on RNA abundances. Amongst these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted EML4 translation and led to widespread EML4 overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics and cell morphology, triggering cellular protrusions and enhancing cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. A METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo. Our findings unveil a dynamic and functional epitranscriptomic landscape in lung adenocarcinoma, pinpointing the hyper-methylation of EML4 as a key driver of tumor metastasis.

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Project description:N6-methyladenosine (m6A) is one of the most popular RNA modifications, which is widely found in messenger RNAs (mRNAs) and non-coding RNA like long no-coding RNA (lncRNAs) and circular RNA (circRNAs).In our study,we provide m6A landscape of human ameloblastoma, which expands the understanding of m6A modifications and uncovers regulation of lncRNAs and circRNAs through m6A modification in ameloblastoma.

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Project description:N⁶-methyladenosine (m6A) and its reader, writer, and eraser (RWE) proteins assume crucial roles in regulating the splicing, stability, and translation of mRNA. To our knowledge, no systematic investigations have been conducted about the crosstalk between m6A and other modified nucleosides in RNA. Herein, we modified our recently established liquid chromatography-parallel-reaction monitoring (LC-PRM) method by incorporating stable isotope-labeled (SIL) peptides as internal or surrogate standards for profiling epitranscriptomic RWE proteins. We were able to detect reproducibly a total of 114 RWE proteins in HEK293T cells with the genes encoding m6A eraser proteins (i.e., ALKBH5, FTO) and the catalytic subunit of the major m6A writer complex (i.e., METTL3) being individually ablated. Notably, eight proteins were altered by more than 1.5-fold in the opposite directions in HEK293T cells depleted of METTL3 and ALKBH5. Analysis of published m6A mapping results revealed the presence of m6A in the corresponding mRNAs of four of these proteins. Together, we integrated SIL peptides into our LC-PRM method for quantifying epitranscriptomic RWE proteins, and our work revealed potential crosstalks between m6A and other epitranscriptomic modifications. Our modified LC-PRM method with the use of SIL peptides should be applicable for high-throughput profiling of epitranscriptomic RWE proteins in other cell types and in tissues.

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The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.